The present invention relates to a nitrogen-containing heterocyclic compound derivative useful as a phosphodiesterase-4 inhibitor, its salt or hydrates thereof, and a medicament comprising the same. More specifically, it relates to a prophylactic and therapeutic agent comprising a nitrogen-containing heterocyclic compound, its salt or hydrates thereof for inflammatory diseases, asthma, autoimmune disease such as allograft rejection, graft versus host disease, chronic joint rheumatism and multiple sclerosis, sepsis, psoriasis, osteoporosis or diabetes.
In a group of a series of decomposition enzymes called phosphodiesterase (referred to hereinafter as xe2x80x9cPDExe2x80x9d), the presence of 7 families of PDE1 to PDE7 is confirmed. One family PDE4 is an enzyme specific to a secondary messenger, cyclic adenosine-3xe2x80x2,5xe2x80x2-monophosphate (cyclic AMP), and is known to regulate the concentration of cyclic AMP by decomposition. Cyclic AMP is increased in vivo upon stimulation with hormone, to exhibit a wide variety of physiological actions such as formation of specific enzymes or regulation of metabolic functions, and in e.g. human leukocytes, cyclic AMP has an important role in activation of cells and regulation of immune response. Under this background, the physiological significance of PDE4 has been regarded as important in recent years, and it is expected that a PDE4 inhibitor can work effectively as a prophylactic and therapeutic agent against various diseases in which cyclic AMP is involved. For example, since PDE4 is present widely in mast cells eosinophils monocytes macrophages T-lymphocytes, epithelial cells, and respiratory smooth muscles, there have been proposed the possibility of the PDE4 inhibitor as an anti-asthma agent (Clin. Exp. Allergy, 22, 337-44, 1992) and the possibility of the PDE4 inhibitor as an agent for treating arthritis, cachexia, multiple sclerosis and sepsis on the basis of a report on the inhibition of tumor-necrosis-factor xcex1 (TNFxcex1) by the PDE4 inhibitor (Int. J. Immunopharmacol., 15, 409-13, 1993; Int. J. Immunopharmacol., 16, 805-16, 1994). With these findings as the background, a large number of reports on those compounds inhibiting PDE4 have been made. For example, JP-A 5-229987 and JP-A 9-59255 disclose an invention relating to naphthalene compounds as PDE4 inhibitors. On the other hand, JP-B 40-20866 and JP-B 6-192099 disclose an invention relating to quinazoline compounds as inhibitors of production of TNFxcex1.
Heretofore, theophylline is famous as a PDE4 inhibitor, but is poor in specificity for PDE4 and inhibits the PDE family unspecifically, thus bringing about side effects in cardiac blood vessels or in the central system. Further, other PDE4 inhibitors also cause the problems of nausea, emesis, headache etc., and therefore, none of effective PDE4 inhibitors have been created.
Under these circumstances, the present inventors made extensive study for the purpose of providing a PDE4 inhibitor effective for the inflammatory diseases and immune diseases. As a result, they found that a nitrogen-containing heterocyclic compound having a novel structure, its salt or hydrates thereof, exhibit superior activity as a PDE4 inhibitor, and also that it is useful as an inhibitor of production of TNFxcex1. Further, the present inventors found that the PDE4 inhibitor of the present invention has the action of lowering blood sugar and is useful as a prophylactic and therapeutic agent for diabetes. Thus, they have accomplished the present invention.
That is, the present invention relates to a nitrogen-containing heterocyclic compound represented by the following formula, its salt or hydrates thereof, and a medicament comprising the same. 
Wherein the ring A is an aromatic hydrocarbon ring which may have a heteroatom, the ring B represents:
1) a saturated hydrocarbon ring which may have a substituent group,
2) an unsaturated hydrocarbon ring which may have a substituent group,
3) a saturated heterocyclic ring which may have a substituent group or
4) an unsaturated heterocyclic ring which may have a substituent group,
R1 represents:
1) hydrogen atom,
2) a halogen atom,
3) a C1-6 alkyl group which may be substituted with a halogen atom,
4) a C1-6 alkoxy group which may be substituted with a halogen atom or
5) an amino group which may be substituted with a C1-6 alkyl group or an acyl group,
R2 and R3 are the same as or different from and represent:
1) hydrogen atom,
2) a C1-6 alkyl group which may have a substituent group,
3) a C3-7 cycloalkyl group which may have a substituent group,
4) a C2-6 alkenyl group which may have a substituent group or
5) an acyl group,
R4, R5, R6 and R7 are the same as or different from and represent:
1) hydrogen atom,
2) a halogen atom,
3) a C1-6 alkyl group which may be substituted with a halogen atom,
4) a C3-7 cycloalkyl group which may have a substituent group,
5) an aryl group which may have a substituent group,
6) a C1-6 alkoxy group which may have a substituent group,
7) a C3-7 cycloalkoxy group which may have a substituent group,
8) an aryl alkoxy group which may have a substituent group, or
9) a C1-6 alkylthio group which may have a substituent group,
10) a hydroxyl group,
11) an amino group which may be substituted with a C1-6, alkyl group or an acyl group,
12) a nitro group,
13) a cyano group,
14) a carboxyl group or
15) a C1-6 alkoxy carbonyl group, or
16) neighboring R3, R4, R5 and R6 may be combined to form a ring which may be substituted with a C1-6 alkyl group, and the ring being a ring which may form a heterocyclic ring containing one or more atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
L represents:
1) a single bond,
2) a C1-6 alkylene group which may have a substituent group,
3) a C2-6 alkenylene group which may have a substituent group,
4) a C2-6 alkynylene group which may have a substituent group, or
5) a group represented by the formula xe2x80x94Exe2x80x94Gxe2x80x94 (wherein E represents:
a) an oxygen atom,
b) a sulfur atom,
c) formula xe2x80x94COxe2x80x94,
d) xe2x80x94SOxe2x80x94,
e) xe2x80x94SO2xe2x80x94,
f) xe2x80x94N(R8)xe2x80x94 (wherein R8 represents hydrogen atom, a C1-6 alkyl group or an acyl group),
g) xe2x80x94N(R9)xe2x80x94COxe2x80x94 (wherein R9 represents hydrogen atom or a C1-6 alkyl group) or
h) xe2x80x94(CH2)mxe2x80x94 which may have a substituent group (wherein m is an integer of 0 to 6), and
G represents:
a) a sulfonyl group,
b) formula xe2x80x94N(R10)xe2x80x94 (wherein R10 represents hydrogen atom, a C1-6 alkyl group or an acyl group), or
c) xe2x80x94(CH2)nxe2x80x94 (wherein n is an integer of 0 to 6)), and X and Y are the same as or different from each other and each represents:
1) a nitrogen atom,
2) xe2x95x90CHxe2x80x94 or
3) a carbon atom which may be substituted with a C1-6 alkyl group which may have a substituent group, provided that X and Y are not simultaneously carbon atoms which may be substituted with a C1-3 alkyl group.
Preferably, X and/or Y is a nitrogen atom.
Further, the present invention provides a phosphodiesterase-4 inhibitor comprising the above-mentioned nitrogen-containing heterocyclic compound, its salt or hydrates thereof. In addition, it provides an inhibitor of production of TNFxcex1, comprising the above-mentioned nitrogen-containing heterocyclic compound, its salt or hydrates thereof. Furthermore, it provides a pharmaceutical composition comprising a pharmacologically effective amount of the above-mentioned nitrogen-containing heterocyclic compound, its salt or hydrates thereof and a pharmaceutically acceptable carrier. Also, it provides a method of preventing or treating diseases against which an inhibitory action on phosphodiesterase-4 is effective for therapy, which comprises administering a pharmacologically effective amount of the above-mentioned nitrogen-containing heterocyclic compound, its salt or hydrates thereof to a patient for whom an inhibitory action on phosphodiesterase-4 is effective for therapy. Further, it provides use of the above-mentioned nitrogen-containing heterocyclic compound, its salt or hydrates thereof in production of a phosphodiesterase-4 inhibitor.
The present invention also encompasses nitrogen-containing heterocyclic compound shown in the following mode, its salt or hydrates thereof.
That is, in the formula, the ring A is a monocyclic or bicyclic aryl group which may have a substituent group and a heteroatom, the ring B represents:
1) a C3-7 cycloalkyl group which may have a substituent group and a heteroatom, or
2) a monocyclic or bicyclic unsaturated cycloalkyl group which may have a substituent group and a heteroatom, R1 represents:
1) a hydrogen atom,
2) a halogen atom,
3) a straight-chain or branched C1-6 alkyl group which may be substituted with a halogen atom,
4) a C1-6 alkoxy group which may be substituted with a halogen atom, or
5) an amino group which may be substituted with a C1-6 alkyl or acyl group,
R2 and R3 are the same or different and represent:
1) hydrogen atom,
2) a straight or branched C1-6 alkyl group which may be substituted with a halogen atom,
3) a C3-7 cycloalkyl group,
4) a C2-4 alkenyl group, or
5) an acyl group,
R4, R5, R6 and R7 are the same or different and represent:
1) hydrogen atom,
2) a halogen atom,
3) a straight or branched C1-6 alkyl group which may be substituted with a halogen atom,
4) a C3-7 cycloalkyl group,
5) an aryl group which may have a substituent group,
6) a C1-6 alkoxy group which may be substituted with a halogen atom,
7) a C3-7 cycloalkoxy group,
8) an aryl alkoxy group which may have a substituent group,
9) a C1-6 alkylthio group,
10) a hydroxy group,
11) an amino group which may be substituted with a C1-6 alkyl group or an acyl group,
12) a nitro group,
13) a cyano group,
14) a carboxyl group or
15) a C1-6 alkoxycarbonyl group, or
16) neighboring R3, R4, R5 and R6 may be combined to form an alkylene dioxy ring which may be substituted with a C1-3 alkyl group,
L represents:
1) a C1-6 alkylene group which may have a substituent group,
2) a C2-6 alkenylene group which may have a substituent group,
3) a C2-6 alkynylene group which may have a substituent group, or
4) formula xe2x80x94Exe2x80x94Gxe2x80x94, (wherein E represents:
a) an oxygen atom,
b) a sulfur atom which may be oxidized,
c) an alkylene group represented by the formula xe2x80x94(CH2)mxe2x80x94 which may have a substituent group, wherein m is 0 or an integer of 1 to 6,
d) a group shown in the formula xe2x80x94COxe2x80x94,
e) a group represented by the formula xe2x80x94N(R8)xe2x80x94 (wherein R8 represents hydrogen atom, a C1-6 alkyl group or an acyl group), or
f) a group represented by the formula xe2x80x94N(R9)xe2x80x94 (wherein R9 represents a hydrogen atom or a C1-6 alkyl group, and
G represents:
a) a sulfonyl group,
b) formula xe2x80x94N(R10)xe2x80x94 (wherein R10 represents hydrogen atom, a C1-6 alkyl group or an acyl group), or
c) formula xe2x80x94N(CH2)nxe2x80x94 (wherein n is 0 or an integer of 1 to 6), provided that when both E and G are alkylene groups, L is a C1-6 alkylene group), and
X and Y are the same as or different from each other and each represent:
1) a nitrogen atom, or
2) a carbon atom which may be substituted with a C1-6 alkyl group, provided that X and Y are not simultaneously carbon atoms which may be substituted with a C1-3 alkyl group.